Cyclosporin A is the active Ingredient in RESTASIS®, a topical ocular formulation approved in the United States for the treatment of dry eye. Topical cyclosporin is also used in the management of other ophthalmic conditions such as restoration of corneal sensitivity following refractive surgery, conjunctival and corneal inflammation, keratoconjuntivitis, graft versus host disease, post-transplant glaucoma, corneal transplants, mycotic keratitis, meibomian gland dysfunction, Thygeson's superficial punctate keratitis, uveitis, and Theodore's superior limbic keratoconjunctivitis.
Patient compliance is extremely important but many patients fail to comply with ocular medications. Moreover, some treatments for conditions other than dry eye dose more frequently than the twice-a-day dosing approved for RESTASIS®, and concentrations of cyclosporin A higher in tissue than RESTASIS® can deliver after multiple dosing would be beneficial to certain patients with severe conditions, such as graft vs. host disease. Some ocular diseases may require long-term therapy. For example, the National Eye Institute (NEI) has completed a study to evaluate 1 and 2 mg biodegradable implants of cyclosporin to treat uveitis. The NEI is also studying the use of non-degradable cyclosporin implants for treatment of graft vs. host disease. However, it should be noted that removing non-degradable implants after the dose has been depleted requires a second surgery. Some other relevant studies also have been conducted by the NEI or are in the process of recruiting patients for studies. Results for these NEI studies have not been published.
A single implantation or injection, which delivers high levels of cyclosporin constantly over a long period (weeks or months) is desirable. The use of multi-month biodegradable or bioerodible delivery system, which delivers cyclosporin to targeted anterior ocular tissues—at equal or greater concentration as RESTASIS®—is clearly desirable. It is also desirable to have an injectable formulation, which would avoid surgery. A formulation which could pass through a 22 gauge needle (or smaller) and avoid the ocular tissue damage which may occur with trocars, larger needles, or surgical implantation, is also desirable.
The reported success of injecting cyclosporin formulations into the conjunctiva for long-duration therapy has been highly limited: while short-term efficacy has been shown with some microspheres and other formulations, no formulation has been demonstrated to be equivalent or superior in delivering cyclosporin to anterior tissue, when compared to RESTASIS® for a period of at least 3 months.
Biodegradable implants, which can be delivered through a 22 gauge needle, do not deliver sufficient drug over a sufficient period of time to meet the need. Biodegradable gel-forming suspensions perform better but, still do not meet the need.
The inventors have surprisingly found that the formulations of the invention, when delivered to the subconjunctival space of the eye through a 22 or smaller gauge needle, deliver cyclosporin A to most anterior ocular tissue for a sustained period of time.